The proposed program will (a) continue to develop the utility and improve the stereocontrol of intramolecular [2+2] photochemical cycloaddition reactions and (b) develop new cyclobutane fragmentation sequences to improve the versatility and importance of intramolecular photocycloadditions, (c) develop new methods for the efficient preparation of highly substituted and functionalized photocycloaddition substrates and (d) demonstrate the synthetic potential of photocycloaddition-cyclobutane motivation strategies through their application to the total synthesis of biologically active and structually complex naturally occurring materials. The completion of the total synthesis of ginkgolide B,3-5 as well as further investigation of stereochemical control in photocycloadditions with 4 atom tethers (1,7-enone-olefins) in the context of synthetic approaches to taxusin, and paniculatine. An expansion of the conjugate addition-cyclization of functionalized zinc reagents to include the preparation of highly functionalized, six membered and possibly larger rings through the use of substituted zinc-copper homoenolate reagents will be investigated. A novel strategy for entry into crossed adducts of intramolecular photocycloadditions will be explored and applied to a synthesis of the novel natural products CP-263,114 and CP-225,917 which inhibit squalene synthase and ras farnesyl transferase. Also, two new approaches to chiral auxiliary mediated asymmetric induction in both intermolecular and intramolecular photocycloadditions will be investigated in an attempt to control absolute asymmetry through photocycloadditions. The recently developed radical initiated cyclobutane fragmentation for the preparation of medium rings will be utilized in a synthesis of taxusin. Promising preliminary results for the enantioselective synthesis of eight and nine membered cyclic ethers will be further investigated. A practical asymmetric aldol will be further refined for aldol additions of alkenyl glycolates of oxazolidinethiones and thiazolidinethiones. An anti selective variant of the oxazolidinethione aldo will be investigated. The synthesis of laurencin, and laurallene will be pursued to demonstrate the potential of the aldol- metathesis combination.